A-M. Vandamme et al. (Antiviral Chemistry & Chemotherapy, 1998 9:187-203) describe current HAART clinical treatments of HIV-1 infections in man including triple drug combinations. Highly active anti-retroviral therapy (HAART) has traditionally consisted of combination therapy with nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). These compounds inhibit biochemical processes required for viral replication. In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. While HAART has dramatically altered the prognosis for HIV infected persons, there remain many drawbacks to the current therapy including highly complex dosing regimes and side effects which can be very severe (A. Carr and D. A. Cooper, Lancet 2000 356(9239):1423-1430). Moreover, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance, thus limiting their utility in long term therapy. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
The chemokines, a subset of the cytokine family of soluble immune modulators, are a large family of pro-inflammatory peptides that exert their pharmacological effect through G-protein-coupled receptors. The name “chemokine”, is a contraction of “chemotactic cytokines”. The chemokines are leukocyte chemotactic proteins capable of attracting leukocytes to various tissues, which is an essential response to inflammation and infection. Human chemokines include approximately 50 structurally homologous small proteins comprising 50-120 amino acids. (M. Baggiolini et al., Ann. Rev. Immunol. 1997 15:675-705) The CCR5 receptor is one member of this family.
Chemokine receptors are seven membrane-spanning receptors that signal through heterotrimeric G protein when bound to an agonist. Human CCR5 is composed of 352 amino acids with an intra-cellular C-terminus containing structural motifs for G-protein association and ligand-dependent signaling (M. Oppermann Cellular Signaling 2004 16:1201-1210). The extracellular N-terminal domain contributes to high-affinity chemokine binding and interactions with the gp120 HIV protein (T. Dragic J. Gen. Virol. 2001 82:1807-1814; C. Blanpain et al. J. Biol. Chem. 1999 274:34719-34727). The natural ligands for the CCR5 are the macrophage inflammatory proteins (MIP) designated MIP-1a and MIP-1b and RANTES. The binding site for RANTES (Regulated upon Activation and is Normal T-cell Expressed and Secreted) has been shown to be on the N-terminal domain and HIV gp120 has been suggested to interact initially with the N-terminal domain and also with the ECL2 (extra-cellular loop 2). (B. Lee, et al. J. Biol. Chem. 1999 274:9617-26)
Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV-1 and genetically related retroviruses. As leukocyte chemotactic factors, chemokines play an indispensable role in the attraction of leukocytes to various tissues of the body, a process which is essential for both inflammation and the body's response to infection. Because chemokines and their receptors are central to the pathophysiology of inflammatory, autoimmune and infectious diseases, agents which are active in modulating, preferably antagonizing, the activity of chemokines and their receptors, are useful in the therapeutic treatment of these diseases. The CCR5 receptor is of particular importance in the context of treating inflammatory and infectious diseases.
HIV-1 infects cells of the monocyte-macrophage lineage and helper T-cell lymphocytes by exploiting a high affinity interaction of the viral enveloped glycoprotein (Env) with the CD4 antigen. The CD4 antigen, however, appeared to be a necessary, but not sufficient requirement for cell entry and at least one other surface protein was required to infect the cells (E. A. Berger et al., Ann. Rev. Immunol. 1999 17:657-700). Two chemokine receptors, either the CCR5 (M-trophic strains) or the CXCR4 (T-trophic strains) receptor were subsequently found to be co-receptors which are required, along with CD4, for infection of cells by the human immunodeficiency virus (HIV). The central role of CCR5 in the pathogenesis of HIV was inferred by epidemiological identification of powerful disease modifying effects of the naturally occurring null allele CCR5 Δ32. The Δ32 mutation has a 32-base pair deletion in the CCR5 gene resulting in a truncated protein designated Δ32. Relative to the general population, Δ32/Δ32 homozygotes are significantly common in exposed/uninfected individuals suggesting the role of CCR5 in HIV cell entry (R. Liu et al., Cell 1996 86(3):367-377; M. Samson et al., Nature 1996 382(6593):722-725).
The HIV-1 envelope protein is comprised of two subunits: gp120, the surface subunit and gp41, the transmembrane subunit. The two subunits are non-covalently associated and form homotrimers which compose the HIV envelope. Each gp41 subunit contains two helical heptad repeat regions, HR1 and HR2 and a hydrophobic fusion region on the C-terminus.
Viral fusion and cell entry is a complex multi-step process and each step affords the potential for therapeutic intervention. The CD4 binding site on the gp120 of HIV appears to first interact with the CD4 molecule on the cell surface inducing a conformation change in gp120 which creates or exposes a cryptic CCR5 (or CXCR4) binding site, and undergoes conformational changes which permits binding of gp120 to the CCR5 and/or CXCR4 cell-surface receptor. The bivalent interaction brings the virus membrane into close proximity with the target cell membrane and the hydrophobic fusion region can insert into the target cell membrane. A conformation change in gp41 creates a contact between the outer leaflet of the target cell membrane and the viral membrane which produces a fusion pore whereby viral core containing genomic RNA enters the cytoplasm. The conformational changes induced by these steps expose additional targets for chemotherapeutic intervention. Each of these steps affords an opportunity for therapeutic intervention in preventing or slowing HIV infection.
Small molecules (Q. Guo et al. J. Virol. 2003 77:10528-63) and antibodies (D. R. Kuritzkes et al. 10th Conference on Retroviruses and Opportunistic Infections, Feb. 10-14, 2003, Boston, Mass. Abstract 13; K. A. Nagashima et al. J. Infect. Dis. 2001 183:1121-25) designed to prevent the gp120/CD4 interaction have been disclosed. Small molecule antagonists of, and antibodies to, CCR5 are discussed below. A small molecular weight antagonist of CXCR4 has been explored (J. Blanco et al. Antimicrob. Agents Chemother. 2000 46:1336-39). Enfuvirtide (T20, ENF or FUZEON®) is a 36 amino acid peptide corresponding to residues 643-678 in the HR2 domain of gp41. Enfuvirtide binds to the trimeric coiled-coil by the HR1 domains and acts in a dominant negative manner to block the endogenous six helix bundle formation thus inhibiting viral fusion. (J. M. Kilby et al., New Eng. J. Med. 1998 4(11):1302-1307). Enfuvirtide has been approved for clinical use.
Potential CCR5 antagonists have been reviewed. (A. Palani and J. R. Tagat, “Discovery and Development of Small-Molecule Chemokine Coreceptor CCR5 Antagonists” J. Med. Chem. 2006 49(10):2851-2857; J. D. Reeves and A. J. Piefer, “Emerging Drug Targets for Antiviral Therapy” Drugs 2005 65(13):1747-1766; M. Westby and E. van der Ryst, “CCR5 antagonists: Host-targeted antivirals for the treatment of HIV infection” Antiviral Chem. Chemother. 2005 16(6):339-354; B. Juelg and F.-D., “CCR5 antagonists: a new tool in fighting HIV” J. HIV Ther. Current Trends 2005 10(4):68-71).
Takeda identified TAK-779 as a potential CCR5 antagonist. (M. Shiraishi et al., J. Med. Chem. 2000 43(10):2049-2063; M. Babba et al. Proc. Nat. Acad. Sci. USA 1999 96:5698-5703) and TAK-220 (C. Tremblay et al. Antimicrob. Agents Chemother. 2005 49(8):3483-3485). WO0039125 (D. R. Armour et al.) and WO0190106 (M. Perros et al.) disclose heterocyclic compounds that are potent and selective CCR5 antagonists. Pfizer has received FDA approval to market miraviroc (UK-427,857; SELZENTRY®, CELZENTRY®) for treatment of HIV-1 infections and AIDS (P. Dorr et al., Antimicrob. Agents Chemother. 2005 49(11):4721-4732; A. Wood and D. Armour, Prog. Med. Chem. 2005 43:239-271; C. Watson et al., Mol. Pharm. 2005 67(4):1268-1282; M. J. Macartney et al., 43rd Intersci. Conf. Antimicrob. Agents Chemother. Sep. 14-17, 2003, Abstract H-875). Schering has advanced Sch-351125 (SCH-C) into Phase I/II clinical studies and reported the advance of a more potent follow-up compound, Vicroviroc (Sch-417690, SCH-D) into Phase I studies (S. W. McCrombie et al., WO00066559; B. M. Baroudy et al. WO00066558; A. Palani et al., J. Med. Chem. 2001 44(21):3339-3342; J. R. Tagat et al., J. Med. Chem. 2001 44(21):3343-3346; J. A. Esté, Cur. Opin. Invest. Drugs 2002 3(3):379-383; J. M. Struzki et al. Proc. Nat. Acad. Sci. USA 2001 98:12718-12723). Merck has disclosed the preparation of (2S)-2-(3-chlorophenyl)-1-N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzothiophene-3,4′-piperidin-1′-yl)butane S-oxide and related derivatives with good affinity for the CCR5 receptor and potent-HIV activity. (P. E. Finke et al., Bioorg. Med. Chem. Lett., 2001 11:265-270; P. E. Finke et al., Bioorg. Med. Chem. Lett., 2001 11:2469-2475; P. E. Finke et al., Bioorg. Med. Chem. Lett., 2001 11:2475-2479; J. J. Hale et al., Bioorg. Med. Chem. Lett., 2001 11:2741-22745; D. Kim et al., Bioorg. Med. Chem. Lett., 2001 11:3099-3102) C. L. Lynch et al. Org. Lett. 2003 5:2473-2475; R. S. Veazey et al. J. Exp. Med. 2003198:1551-1562. GSK-873140 (ONO-4128, E-913, AK-602) was identified in a program initiated at Kumamoto University (K. Maeda et al. J. Biol. Chem. 2001 276:35194-35200; H. Nakata et al. J. Virol. 2005 79(4):2087-2096) and has been advanced to clinical trials. In WO2004/054974 published Jul. 1, 2004 and in WO2004/055016 published Jul. 1, 2004, W. M. Kazmierski et al. disclose CCR5 antagonists. In WO00/166525; WO00/187839; WO02/076948; WO02/076948; WO02/079156, WO2002070749, WO2003080574, WO2003042178, WO2004056773, WO2004018425 and WO2006/001751 AstraZeneca disclose 4-amino piperidine compounds which are CCR5 antagonists.
In U.S. Publication No. 20050176703 published Aug. 11, 2005, S. D. Gabriel and D. M. Rotstein disclosed heterocyclic CCR5 antagonist capable of prevent HIV cell entry. Related octahydro-pyrrolo[3,4-c]pyrrole compounds which are antagonists of the CCR5 receptor have been disclosed in Assignee's copending non-provisional application US 20060014767 filed Jun. 8, 2005 (WO 2005121145, published Dec. 22, 2005) entitled Heterocyclic Antiviral Compounds, in the names of E. K. Lee et al. published Dec. 22, 2005; U.S. Ser. No. 11/706,807, filed Feb. 15, 2007, entitled Heterocyclic Antiviral Compounds in the names of R. Lemoine et al.; and U.S. Ser. No. 11/706,728, filed Feb. 15, 2007, entitled Heterocyclic Antiviral Compounds in the names of R. Lemoine et al. which are all hereby incorporated by reference in their entirety. In addition to the potential for CCR5 modulators in the management of HIV infections, the CCR5 receptor is an important regulator of immune function and compounds of the present invention may prove valuable in the treatment of disorders of the immune system. Treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis by administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of the present invention is also possible. (M. A. Cascieri and M. S. Springer, Curr. Opin. Chem. Biol. 2000 4:420-427; A. Proudfoot et al., Immunol. Rev. 2000 177:246-256; P. Houshmand and A. Zlotnik, Curr. Opin. Chem. Biol. 2003 7:457-460)